Table 1.
Summary of commercial LMWH and ULMWH production methods and structural characteristics including molecular weight range, chain end groups, anti-coagulant activity (anti-Xa, anti-IIa), and degree of sulfation
| LMWH/ULMWH (INN) | Brand name | Manufacturer/marketing company | Mode of depolymerization/method of preparation | MW (Da) | MW (Da) | NRE | RE | Anti-Xa:anti-IIa ratio | Anti-Xa activity (IU/mg) | Anti-IIa activity (IU/mg) | Degree of sulfation/saccharide unit |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dalteparin sodium |
Fragmin Boxol FR 860 Tedelparin |
Pfizer/Kabi/Pharmacia-Upjohn (US) | Deaminative cleavage with nitrous acid (HONO) | 5600–6400 | 6000–5000 | 2-O-sulfo-α-L-idopyranosuronic acid | 6-O-sulfo-2,5-anhydro-D-mannitol | 1.9–3.2:1 | 110–210 | 35–100 | 2.0–2.5 |
| Enoxaparin sodium |
Lovenox Clexane |
Sanofi-Aventis /Rhone-Poulenc/Aspen Pharma/Eurofarma Lab | Alkaline ß-eliminative cleavage of benzyl ester of heparin | 3500–5500 | 4500 | 2-O-sulfo-4-enepyranosuronic acid (or 2-sulfated 4,5-unsaturated uronic acid) | 2-N-sulfated-D-glucosamine; characterized by 1,6-anhydro ring structure/2-N,6-O-disulfo-D-glucosamine | 3.3–5.3:1 | 100–210 | 20–35 | ~ 2.0 |
| Tinzaparin sodium |
Innohep Logiparin |
LEO Pharma/Novo Nordisk/Braun/DuPont/Pharmion | ß-eliminative cleavage by heparinase/ | 5500 to 7500 | 6500 | 2-O-sulfo-4-enepyranosuronic acid (or 2-sulfated 4,5-unsaturated uronic acid) | 2-N,6-O-disulfo-D-glucosamine | 1.5–2.5:1 | 70–120 | 45–50 | 2.66 |
| Nadroparin calcium |
CY-216 Fraxiparin Seleparina |
Sanofi-Winthrop/Choay/Aspen/Italfarmaco | Deaminative cleavage with nitrous acid (HONO) | 4200 to 5500 | 4300 | 2-O-sulfo-α-L-idopyranosuronic acid | 6-O-sulfo-2,5-anhydro-D-mannitol | 2.5–4.0:1 | 95–130 | 27–37 | 2.0–2.5 |
| Bemiparin sodium |
Badyket Ivor Zibor Hibor Beparine |
Laboratorios Farmaceuticos Rovi S.A. /Sigma Tau/UCB /Biological Evans | Alkaline treatment with quaternary ammonium (NH4) salt of heparin | 3000 to 4200 | 3600 | 2-O-sulfo-4-enepyranosuronic acid | 2-N,6-O-disulfo-D-glucosamine | 8.0:1 | 80–100 | 10–12.5 | About 2 (WHO) |
| Sevuparin (DF02) | N/A | Modus Therapeutics AB/Dilafor AB | Selective oxidation of non-sulfated uronic acid residues in heparin by periodate | 6500 to 9500 | 5000 | 2-N,6-O-disulfo-D-glucosamine |
Glucosamine bound to a “remnant” residue (remnant = D-threonic acid)*
|
1.5:1 | < 10 | < 10 | 2.4 |
| Parnaparin sodium |
Alpha LMWH 86–02 Fluxum Minidalton OP-21–23 |
Alfa Wassermann SpA | Oxidative depolymerization with cupric ions (Cu2+) and hydrogen peroxide (H2O2) | 4500 to 5000 | 5000 | 2-O-sulfo-α-L-idopyranosuronic acid | 2-N,6-O-disulfo-D-glucosamine | 1.5–3.0:1 | 75–110 | 25–30 | 2.15 |
| Reviparin sodium |
Clivarin LU 473,111 |
Knoll AG/Abbott GmbH | Deaminative cleavage with nitrous acid (HONO) | 3400 to 4650 | 3900 | 2-O-sulfo-α-L-idopyranosuronic acid | 6-O-sulfo-2,5-anhydro-D-mannitol | 4.2:1 | 124 | 29 | 2.0–2.6 |
|
Ardeparin sodium (withdrawn from US market in 2000) (www.drugs.com) |
Normiflo RD 11,885 WY-90493-RD |
Wyeth-Ayerst/Hepar Industries/Pfizer | Oxidative depolymerization with hydrogen peroxide (H2O2) | 2000 to 15,000 | 5300–6500 | 2-O-sulfo-α-L-idopyranosuronic acid or saturated uronic acid | 2-N-acetyl-6-O-sulfo-D-glucosamine | 1.8:1 | 95–145 | 45–75 | 2.0–2.7 |
| Certoparin sodium |
Alphaparin Sandoparin Mono-Embolex NM, Troparin |
Novartis/Sandoz/Aspen in EU | Deaminative cleavage with isoamyl nitrite | 4200–6200 | 5200 | 2-O-sulfo-α-L-idopyranosuronic acid | 6-O-sulfo-2,5-anhydro-D-mannitol | 1.5–2.5:1 | 80–120 | 30–35 | 2.0–2.5 |
| Fondaparinux sodium | Arixtra | Aspen | Chemically synthesized by O-sulfation-hydrogenation-N-sulfation of pentasaccharide | 1500–3000 | 1728 | 2-N,6-O-disulfo-D-glucosamine | Methyl-2-N,6-O-disulfo-D-glucosamine (or 6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside) | Specific FXa inhibitor* | 930 | 0 | 1.6 |
|
AVE5026* (A derivative of enoxaparin) |
Semuloparin | Sanofi-Aventis | Chemoselective depolymerization by BEMP following ß-elimination | 2000 to 3000 | 2400 | 2-O-sulfo-4-enepyranosuronic acid (or 4,5 unsaturated uronic acid or 4-enopyranosyl uronate) | - | > 30:1 | 150–200 | 0.2 or < 5 | 2.2 |
|
RO-14 (A derivative of bemiparin) |
N/A | Laboratorios Farmaceuticos Rovi S.A | Chemoselective depolymerization of heparin in non-aqueous medium following ß-elimination | 1800 to 3000 | 2200 | 2-O-sulfo-α-L-idopyranosuronic acid (or 4-enopyranosyl uronate) | 2-N,6-O-disulfo-D-glucosamine | 9.7:1 | 80–140 | ≤ 10 | 2.0 |
Sources: Min Qiu, Shengjie Huang, Chuanhong Luo, Zhenfeng Wu, Binzhu Liang, Haozhou Huang, Zhimin Ci, Dingkun Zhang, Li Han, Junzhi Lin, Pharmacological and clinical application of heparin progress: An essential drug for modern medicine, Biomedicine & Pharmacotherapy 139 (2021) 111,561; Yan Y, Ji Y, Su N, Mei X, Wang Y, Du S, Zhu W, Zhang C, Lu Y, Xing XH. Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders: A review. Carbohydr Polym. 2017 Mar 15;160:71–81. https://doi.org/10.1016/j.carbpol.2016.12.037. Epub 2016 Dec 21. PMID: 28,115,102; Hao, C., Sun, M., Wang, H., Zhang, L., & Wang, W. (2019). Low molecular weight heparins and their clinical applications. Progress in Molecular Biology and Translational Science.https://doi.org/10.1016/bs.pmbts.2019.02.003; Akhtar F, Wan X, Wu G, Kesse S, Wang S, He S. Low-Molecular-Weight Heparins: Reduced Size Particulate Systems for Improved Therapeutic Outcomes. Molecules. 2018 Jul 18;23(7):1757. https://doi.org/10.3390/molecules23071757. PMID: 30,021,958; PMCID: PMC6100363; Lühn S, Grimm JC, Alban S. Simple and rapid quality control of sulfated glycans by a fluorescence sensor assay–exemplarily developed for the sulfated polysaccharides from red algae Delesseria sanguinea. Mar Drugs. 2014 Apr 10;12(4):2205–27. https://doi.org/10.3390/md12042205. PMID: 24,727,392; PMCID: PMC4012468; Bisio A, Urso E, Guerrini M, de Wit P, Torri G, Naggi A. Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies. Molecules. 2017 Jun 24;22(7):1051. https://doi.org/10.3390/molecules22071051. PMID: 28,672,818; PMCID: PMC6152074; *Gerotziafas GT, Petropoulou AD, Verdy E, Samama MM, Elalamy I. Effect of the anti-factor Xa and anti-factor IIa activities of low-molecular-weight heparins upon the phases of thrombin generation. J Thromb Haemost. 2007 May;5(5):955-62. 10.1111/j.1538-7836.2007.02477.x
BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,2,3-diaza-phosphorine
*Source: WO2009007224A1; NIH — National Center for Advancing Translational Sciences, Inxight: Drugs;, https://drugs.ncats.io/substance/V72OT3K19I, accessed: June 30, 2022